The incidence of esophageal adenocarcinomas (EAC) has increased at an alarming rate (>400%) in the last few decades far exceeding any other cancer type in the United States, while the prognosis has remained poor (1). Most EACs are initiated by replacement of normal squamous epithelium with metaplastic mucosa known as Barrett's esophagus (BE), which subsequently progress through a dysplastic stage into invasive carcinomas (2). Although BE-affected individuals carry a 30-125 fold greater risk of developing EAC when compared to an age-matched population (3), the estimated rate of cancer progression among BE individuals is only 1 per 200 patient-years (2). This makes it difficult to identify BE patients who are at an increased risk for cancer development, and is one of the major clinical challenges in this disease. Endoscopy-based surveillance in BE patients has shown only a minimal impact in reducing cancer mortality, and is certainly not cost-effective (2). Though histology based evaluation for high-grade dysplasia (HGD) is currently used for assessing cancer risk in patients with BE, the approach is not optimal owing both to the marked inter-observer variability in interpreting dysplasia (4), and to the highly variable rates of progression to EAC (16-50% over 7 years) among HGD cases (2). Therefore, identification of novel biomarkers that reliably aid in risk stratification in BE would allow for the development of more rational surveillance strategies aimed at early cancer detection, in addition to providing a novel class of therapeutic targets for this deadly disease. Moreover, it will additionally help in curtailing health care costs by refining current screening and surveillance programs. Accordingly, the primary objective of this proposal is to identify RNA-based biomarkers associated with the risk of malignant progression in BE.